In the process of eliminating cancer cells or chronic viral infections, T cell exhaustion might occur due to the overexpression of coinhibitory receptors such as PD-1 and CTLA-4, rendering T cell inactive and failure to combat diseases. Many cancer therapies were developed based on the principle of blocking coinhibitory molecule on the surface of exhausted T cells. However, partial clinical responses on patients suggest that more receptors might be responsible in the induction of T cell exhaustion, suggesting that combined therapeutic programs might be necessary.